The studies proposed constitute an extension of our investigation of the pathogenesis and pathophysiology of clinical disorders of renal acidification. In patients with Type 1 (distal) renal tubular acidosis (RTA), studies have been designed to determine: (a) whether the impairment of H ion secretion in the distal nephron reflects a reduction in the rate-capacity of the H ion secretory process or a limitation on its ability to generate transepithelial H ion concentration gradients; (b) the mechanism of the urine pH-lowering effect of ethacrynic acid, an agent known to inhibit electrogenic chloride reabsorption in the loop of Henle; (c) whether primary disturbances occur in renal tubular transport of potassium and/or chloride. In patients with Type 2 (proximal) RTA, studies have been designed to investigate the mechanism of the reported ameliorative effect of hydrochlorothiazide, and to characterize and quantitate the renal and systemic acid-base and electrolyte effects of chronic administration of this agent. In 12 identified infants and children presenting with renal hyperchloremic acidosis associated with persistent hyperkalemia (so-called Type 4 RTA), studies have been designed to investigate the physiological character and natural history of the renal acidification dysfunction. In these studies, and in the studies described in patients with Type 1 and 2 RTA, the functional activity and pathogenetic role of the renin-angiotensin-aldosterone system will be defined, and in the patients with Type 2 RTA the role of renal prostaglandins.